YY1's role in DNA methylation of Peg3 and Xist

Unusual clusters of YY1 binding sites are located within several differentially methylated regions (DMRs), including Xist, Nespas and Peg3, which all become methylated during oogenesis. In this study, we performed conditional YY1 knockdown (KD) to investigate YY1's roles in DNA methylation of these DMRs. Reduced levels of YY1 during spermatogenesis did not cause any major change in these DMRs although the same YY1 KD caused hypermethylation in these DMRs among a subset of aged mice. However, YY1 KD during oogenesis resulted in the loss of DNA methylation on Peg3 and Xist, but there were no changes on Nespas and H19. Continued YY1 KD from oogenesis to the blastocyst stage caused further loss in DNA methylation on Peg3. Consequently, high incidents of lethality were observed among embryos that had experienced the reduced levels of YY1 protein. Overall, the current study suggests that YY1 likely plays a role in the de novo DNA methylation of the DMRs of Peg3 and Xist during oogenesis and also in the maintenance of unmethylation status of these DMRs during spermatogenesis

Androgen Receptor Function Links Human Sexual Dimorphism to DNA Methylation

Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS) due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aber

Scapular winging: anatomical review, diagnosis, and treatments

Scapular winging is a rare debilitating condition that leads to limited functional activity of the upper extremity. It is the result of numerous causes, including traumatic, iatrogenic, and idiopathic processes that most often result in nerve injury and paralysis of either the serratus anterior, trapezius, or rhomboid muscles. Diagnosis is easily made upon visible inspection of the scapula, with serratus anterior paralysis resulting in medial winging of the scapula. This is in contrast to the lateral winging generated by trapezius and rhomboid paralysis. Most cases of serratus anterior paralysis spontaneously resolve within 24 months, while conservative treatment of trapezius paralysis is less effective. A conservative course of treatment is usually followed for rhomboid paralysis. To allow time for spontaneous recovery, a 6–24 month course of conservative treatment is often recommended, after which if there is no recovery, patients become candidates for corrective surgery

Testis-specific glyceraldehyde-3-phosphate dehydrogenase: origin and evolution

<p>Abstract</p> <p>Background</p> <p>Glyceraldehyde-3-phosphate dehydrogenase (GAPD) catalyses one of the glycolytic reactions and is also involved in a number of non-glycolytic processes, such as endocytosis, DNA excision repair, and induction of apoptosis. Mammals are known to possess two homologous GAPD isoenzymes: GAPD-1, a well-studied protein found in all somatic cells, and GAPD-2, which is expressed solely in testis. GAPD-2 supplies energy required for the movement of spermatozoa and is tightly bound to the sperm tail cytoskeleton by the additional N-terminal proline-rich domain absent in GAPD-1. In this study we investigate the evolutionary history of GAPD and gain some insights into specialization of GAPD-2 as a testis-specific protein.</p> <p>Results</p> <p>A dataset of GAPD sequences was assembled from public databases and used for phylogeny reconstruction by means of the Bayesian method. Since resolution in some clades of the obtained tree was too low, syntenic analysis was carried out to define the evolutionary history of GAPD more precisely. The performed selection tests showed that selective pressure varies across lineages and isoenzymes, as well as across different regions of the same sequences.</p> <p>Conclusions</p> <p>The obtained results suggest that GAPD-1 and GAPD-2 emerged after duplication during the early evolution of chordates. GAPD-2 was subsequently lost by most lineages except lizards, mammals, as well as cartilaginous and bony fishes. In reptilians and mammals, GAPD-2 specialized to a testis-specific protein and acquired the novel N-terminal proline-rich domain anchoring the protein in the sperm tail cytoskeleton. This domain is likely to have originated by exonization of a microsatellite genomic region. Recognition of the proline-rich domain by cytoskeletal proteins seems to be unspecific. Besides testis, GAPD-2 of lizards was also found in some regenerating tissues, but it lacks the proline-rich domain due to tissue-specific alternative splicing.</p

ANCA-associated vasculitis.

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA+ or ANCA-, respectively). Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys are most commonly and severely affected. AAVs have a complex and unique pathogenesis, with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy, prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit with considerable morbidity from glucocorticoids and other immunosuppressive medications. Current challenges include improving the measures of disease activity and risk of relapse, uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse effects. Meeting these challenges requires a more detailed knowledge of the fundamental biology of AAV as well as cooperative international research and clinical trials with meaningful input from patients

Contact with Counter-Stereotypical Women Predicts Less Sexism, Less Rape Myth Acceptance, Less Intention to Rape (in Men) and Less Projected Enjoyment of Rape (in Women)

Intergroup contact—(positive) interactions with people from different social groups—is a widely researched and strongly supported prejudice-reducing mechanism shown to reduce prejudice against a wide variety of outgroups. However, no known previous research has investigated whether intergroup contact can also reduce sexism against women. Sexism has an array of negative outcomes. One of the most detrimental and violent ones is rape, which is both justified and downplayed by rape myth acceptance. We hypothesised that more frequent, higher quality contact with counter-stereotypical women would predict lower levels of sexism and thus less rape myth acceptance (in men) and less sexualised projected responses to rape (in women). Two studies using online surveys with community samples supported these hypotheses. In Study 1, 170 male participants who experienced more positive contact with counter-stereotypical women reported less intention to rape. Similarly, in Study 2, 280 female participants who experienced more positive contact with counter-stereotypical women reported less projected sexual arousal at the thought of being raped. Thus, the present research is the first known to show that contact could be a potential tool to combat sexism, rape myth acceptance, intentions to rape in men, and sexualisation of rape by women

Mapping of myeloperoxidase epitopes recognized by MPO-ANCA using human-mouse MPO chimers

Myeloperoxidase ( MPO) is one of the major target antigens of antineutrophil cytoplasmic autoantibodies ( ANCA) found in patients with small-vessel vasculitis and pauci-immune necrotizing glomerulonephritis. To date, the target epitopes of MPO-ANCA remain poorly defined. Human MPO-ANCA do not typically bind mouse MPO. We utilized the differences between human and mouse MPO to identify the target regions of MPO-ANCA. We generated five chimeric MPO molecules in which we replaced different segments of the human or mouse molecules with their homologous counterpart from the other species. Of serum samples from 28 patients screened for this study, 43 samples from 14 patients with MPO-ANCA-associated vasculitis were tested against recombinant human and mouse MPO and the panel of chimeric molecules. Sera from 64 and 71% of patients bound to the carboxy-terminus of the heavy chain, in the regions of amino acids 517-667 or 668-745, respectively. No patient serum bound the MPO light chain or the amino-terminus of the heavy chain. All sera bound to only one or two regions of MPO. Although the pattern of MPO-ANCA binding changed over time ( 4-27 months) in 6 of 10 patients with several serum samples, such changes were infrequent. Other target regions of MPO-ANCA may not have been detected due to conformational differences between the native and recombinant forms of MPO. MPO-ANCA do not target a single epitope, but rather a small number of regions of MPO, primarily in the carboxy-terminus of the heavy chain